Melatonin has been shown to exert its biological effects through binding to specific G-protein coupled receptors. Two melatonin receptors have been identified in humans, MT1 (me11a) and MT2 (me11b) (Reppert, S. M. et al. Proc. Natl. Acad. Sci. 1995 92, 8734-8738 and Reppert, S. M. et al. Neuron 1994 13, 1177-1185). Specific [125I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting the melatonin receptors are located within the structures containing the human biological clock. Recent evidence has shown that it is the MT2 receptor that is primarily involved in the regulation of circadian rhythms (Dubocovich, M. L. et al. Adv. Exp. Med. Biol. 1999 460, 181-190), and selective MT2 receptor antagonists have demonstrated the ability to block melatonin-mediated phase advances of circadian rhythms (Dubocovich, M. L. et al. FASEB J. 1998 12, 1211-1219).
Thus, selective MT2 receptor antagonists should be particularly useful for the treatment of sleep and chronobiotic disorders in which uncontrolled or undesirable effects of endogenously secreted melatonin would be advantageously blocked. Other indications affected by melatonin activity include depression, mood disorders, seasonal affective disorder, synchronization of biological rhythms in the blind, jet lag, work shift syndrome, immune disorders, premenstrual syndrome, reproductive disorders, neuroendocrine disorders, and resetting of the biological clock.
The novel tetrahydroisoquinoline compounds disclosed in this invention and the use of all of the tetrahydroisoquinoline compounds disclosed in this invention for treating disorders associated with abnormal melatonin conditions are not taught or suggested by the prior art.
Certain N-acyl-1-phenethyl-1,2,3,4-tetrahydroisoquinolines have been disclosed as alkaloid intermediates and cardiovascular agents. See the following references: Itoh, T. et al. Tetrahedron 2001 57, 8827-8839; Osante, I. et al. European Journal of Organic Chemistry 2001 7, 1267-1277; Venkov, A. P. and Lukanov, L. K. Synth. Commun. 1996 26, 755-62; Ishikawa, K. et al. U.S. Pat. No. 5,362,736, 1994; Ishikawa, K. et al. EP 501693 A1, 1996; Dugar, S. and Kogan, T. U.S. Pat. No. 5,124,337, 1992; Czarnocki, Z. et al. J. Chem. Soc., Chem. Commun. 1987 7, 493-4; Czarnocki, Z. et al. Can. J. Chem. 1987 65, 2356-61; Marino, J. P. and Schwartz, A. Tetrahedron Lett. 1979, 35, 3253-6; Kupchan, S. M. et al. J. Org. Chem. 1978 43, 4076-81; Kupchan, S. M. et al. J. Org. Chem. 1978 43, 4464-8; Kupchan, S. M. et al. J. Chem. Soc., Chem. Commun. 1977 23, 847-8; Kupchan, S. M. et al. J. Org. Chem. 1978 43, 2521-9; Kupchan, S. M. et al. J. Org. Chem. 1976 41, 4049-50; Kupchan, S. M. et al. J. Org. Chem. 1976 41, 4047-9; Leimgruber, W. and Wick, A. E. U.S. Pat. No. 3,922,285, 1975; Marino, J. P. and Samanen, J. M. Tetrahedron Lett. 1973 (46), 4553-6; and Leimgruber, W. and Wick, A. E. Ger. Patent 2214498, 1972.